Bochen Florian, Subedi Saurav, La Manna Federico, Jarrin Sofia, Papapostolou Irida, Kruithof-de Julio Marianna, Peinelt Christine
Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland.
Department for BioMedical Research, Urology Research Laboratory, University of Bern, Bern, Switzerland.
Mol Oncol. 2025 May;19(5):1299-1309. doi: 10.1002/1878-0261.13795. Epub 2025 Jan 16.
Transient receptor potential melastatin-4 (TRPM4) ion channel expression is upregulated in prostate cancer (PCa), contributing to increased cell proliferation, migration, adhesion, epithelial-to-mesenchymal transition, cell cycle shift, and alterations of intracellular Ca signaling. GEO2R platform analysis of messenger RNA (mRNA) expression of ~ 6350 genes in normal and malignant prostate tissue samples from 15 PCa patients demonstrates that TRPM4 expression is upregulated sixfold and is among the most significantly upregulated genes in PCa. We find that absence of TRPM4 reduced PCa tumor spheroid size and decreased PCa tumor spheroid outgrowth. In addition, lack of TRPM4 increased cell death in PCa tumor spheroids, a phenotype that is absent in two-dimensional (2D) cancer cell systems. Lastly, absence of TRPM4 in PCa cells reduced extravasation and metastatic burden in a preclinical zebrafish cancer model. Taken together, our findings show that TRPM4 is an attractive therapeutic target in PCa and highlights the need for future development of pharmacological tools.
瞬时受体电位褪黑素4（TRPM4）离子通道在前列腺癌（PCa）中表达上调，导致细胞增殖、迁移、黏附、上皮-间质转化、细胞周期改变以及细胞内钙信号传导异常增加。利用GEO2R平台对15例PCa患者的正常和恶性前列腺组织样本中约6350个基因的信使核糖核酸（mRNA）表达进行分析，结果显示TRPM4的表达上调了6倍，是PCa中上调最显著的基因之一。我们发现，缺失TRPM4可减小PCa肿瘤球体的大小，并减少PCa肿瘤球体的生长。此外，缺乏TRPM4会增加PCa肿瘤球体中的细胞死亡，这是二维（2D）癌细胞系统中不存在的一种表型。最后，在临床前斑马鱼癌症模型中，PCa细胞中缺失TRPM4可减少外渗和转移负担。综上所述，我们的研究结果表明，TRPM4是PCa中一个有吸引力的治疗靶点，并凸显了未来开发药理工具的必要性。
